THE QUEST FOR MEMORY DRUGS

The practical results of this work, as well as extensive follow-up tests in mice and rats, are several new drugs now in early development at Memory Pharmaceuticals, founded in part by Kandel in 1998. MEM1414, the inheritor of the Aplysia findings, appears to enhance the brain's long-term memory functions; researchers hope it will enhance long-term memory in patients with age-related forgetfulness and even ward off the early stages of Alzheimer's disease, even though the two ailments are not related. There's also MEM1917, a drug similar to 1414; MEM1003, which protects neurons from damaging overloads of calcium, and MEM3454, a schizophrenia treatment that targets a receptor also known to respond to nicotine.

Other companies are also in the hunt. Sention has an intriguing new drug, C105 (which is largely under wraps for now), in clinical trials. Cortex Pharmaceuticals, one of the oldest memory-booster firms, is focusing on molecules called ampakines, which modulate receptors in the brain that can strengthen the synapses. The company already has one drug, CX516, through trials, though it is too weak to be a practical prescription option. A revved-up version, CX717, is in the works, and other firms are developing their own ampakines.

Researchers are reluctant to sing the praises of any of these drugs just yet. A broad class of drugs called nootropics showed potential in the 1970s, but they were "shots in the dark," says Dr. Scott Small of CUMC, and they have since fallen out of favor with mainstream scientists. Alternative medicine has also offered remedies. Ginkgo biloba, the most well known, has been a favorite for centuries. But science has been unable to verify its effectiveness, and supplements sold over the counter are often coy about their contents. Even if ginkgo does work, some pill versions may not contain enough of it to have any effect. The workable alternatives to alternative medicine, until now, have largely been limited to dozens of books containing mental gymnastics, such as crossword puzzles, intended to keep the brain's gears well greased. Eating fish--rich in omega-3 fatty acids--keeps blood vessels in the brain clear of blockages, allowing the nerve cells to function to the best of their abilities. But none of these remedies can completely halt "mild cognitive impairment" in adults; they can only slow it down.

Alternative remedies and brainteasers do have one advantage--they don't raise the troubling prospect of otherwise healthy people using the drugs for a boost, like steroids for geeks. "There's a question of whether we should be in the business of making memory boosters in the first place. Once we're in a gray area we at least need to be careful," says Small. "With people who are impaired by a subtle but real change in their brain function, we might not want to sit in judgment and say, 'No, we can't help you.' But the fact that a high-school student can't do well on the SAT--is that a disease?"

Ethics questions, no matter how valid, aren't likely to keep scientists from doing the basic research that could underlie drug development. There is still much to be learned. Siegelbaum's and Kandel's labs have stumbled on to an intriguing and heretofore unknown property of ion channels, tiny protein-based structures that can transport small charged molecules across the membranes of cells. One particular type of channel is found, among other places, in the hippocampus. Lab-created mice that lack this type of channel seem to be smarter than your average mouse, especially at typical memory-based tasks like repeated mazes. The upshot: when the hippocampal channels are in use, they appear to hinder memory. Siegelbaum suspects that neurotransmitters close the channels, rendering them moot, when the brain needs to remember something, but leave them open otherwise to screen out the ephemera of everyday life, the things that just aren't important enough to remember long-term. If he's right, the channels offer a tantalizing possibility: what if scientists could create a drug that would close them on command, allowing for total recall? "It's a bit of a daunting task," says Siegelbaum. But whether there's a pill at the end or not, it's still great science--and that's always an audacious goal.

© 2004